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WO2009152160A1 - Promédicaments inhalés à base de carbaprostacyclines et de prostacyclines destinés au traitement de l'hypertension artérielle pulmonaire - Google Patents

Promédicaments inhalés à base de carbaprostacyclines et de prostacyclines destinés au traitement de l'hypertension artérielle pulmonaire Download PDF

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WO2009152160A1
WO2009152160A1 PCT/US2009/046764 US2009046764W WO2009152160A1 WO 2009152160 A1 WO2009152160 A1 WO 2009152160A1 US 2009046764 W US2009046764 W US 2009046764W WO 2009152160 A1 WO2009152160 A1 WO 2009152160A1
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optionally substituted
compound
compound according
pcy
independently
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William Baker
Josh Van Veldhuizen
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Gilead Sciences Inc
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Gilead Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • the instant invention relates to the preparation of prodrugs of carbaprostacyclins and prostacyclins for delivery to the lung by aerosolization to effectively treat pulmonary arterial hypertension.
  • Pulmonary Arterial Hypertension (PAH), formerly referred to as Primary Pulmonary Hypertension (PPH), is characterized by continuous high blood pressure in the pulmonary artery. The increased pulmonary vascular resistance leads to right ventricular failure and death. Impaired vascular and endothelial homeostasis may be manifested by reduced synthesis of prostacyclin (PGI 2 ), increased thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin-1 (Giad, A. & Saleh, D. 1995 ⁇ Engl J Med 333:214-221 ; Xue, C & Johns, R. A. 1995 JV Engl J Med 333: 1642- 1644).
  • PKI 2 prostacyclin
  • thromboxane production decreased formation of nitric oxide
  • endothelin-1 (Giad, A. & Saleh, D. 1995 ⁇ Engl J Med 333:214-221 ; Xue, C
  • PAH affects an estimated 50,000 patients in the United States, with only about 15,000 diagnosed and under treatment.
  • the cause of PAH may be unknown or result from other diseases that cause a restriction of blood flow to the lungs, including scleroderma, HIV and lupus. Symptoms of the disease include fatigue, shortness of breath on exertion, chest pain and dizziness. Left untreated, the median survival time following diagnosis may be as short as three years.
  • Flolan must be refrigerated during administration, has a half-life of only 3 to 5 minutes, and must be infused continuously.
  • Alternative prostanoids trepostinil (Remodulin*) and iloprost (Ilomedin ® ) are also used to treat PAH.
  • Trepostinil can be given intravenously or subcutaneously but the subcutaneous form is very painful.
  • An increased risk of sepsis with intravenous treprostinil has been reported by the CDC. Iloprost can be administered intravenously and has a longer half-life than treprostinil.
  • iloprost can be formulated for inhalation (Ventavis ® ).
  • This form of administration has the advantage of selective deposition in the lungs near the site of action of the drug leading to fewer systemic side effects.
  • Ventavis is self- administered 6 to 9 times a day during waking hours and a treatment session requires about 4 to 10 minutes total delivery time. Thus, significant patient time is consumed during the course of the day leading to reduced compliance and insufficient treatment during the sleeping hours.
  • inhaled prostacyclins with a longer duration of action to treat PAH.
  • the instant invention comprises inhalable phenylphosphate-prodrugs of prostacyclins for the treatment of PAH that are activated by phosphatases in the lungs releasing the component prostacyclins.
  • This avoids the peripheral systemic effects of the prostacyclins and provides a sustained release of the prostacyclin.
  • the frequency of administration is reduced compared to the inhaled prostacyclin alone leading to improved patient compliance and improved reduction of the pulmonary blood pressure during the hours of sleep.
  • the invention is a compound of Formula I:
  • each R ! and R 2 is, independently, optionally substituted C 1 -Ci O alkyl, optionally substituted C 2 -C] O alkenyl, optionally substituted C 2 -C]Q alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C f1 -C] 0 aryl, or optionally substituted heteroaryl; or R ! and R 2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S or NR :
  • each G 2 is independently CFb or O; each G 4 is independently optionally substituted Ci-Cg alkylene, optionally substituted C 2 -Cg alkenylene, or optionally substituted C 2 -Cg alkynylene wherein a carbon atom of said optionally substituted Cj-Cg alkylene is, optionally, replaced by O, S, NR 1 ; each G i5" i • s independently a bond or CH 2 ; each R 4 is independently
  • each R 5 is independently optionally substituted Ci-Cs alkyl, optionally substituted C 2 -Cg alkenyl, or optionally substituted C 2 -C & alkynyl wherein a carbon atom of said optionally substituted Ci-Cg alkyl is, optionally, replaced by O, S, NR J ;
  • L is O or -CH 2 O-; and A ⁇ is a pharmaceutically acceptable negative counter ion.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as a liquid or solid dosage form suitable for nebulization, pressurized metered dose inhalation or dry powder delivery.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula ⁇ , or a pharmaceutically acceptable salt thereof, as a liquid or dry powder that can be efficiently aerosolized by metered-dose inhalers; or jet, ultrasonic, pressurized, or vibrating porous plate nebulizers; whereby the predominant aerosol particles produced have a mass median aerodynamic diameter of about 1 to about 5 ⁇ m size range.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the salinity and pH of said composition is adjusted to permit generation of an aerosol well tolerated by patients.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the salinity and pH of said composition is adjusted to permit generation of an aerosol well tolerated by patients and provides optimal conditions for the activity of lung phosphatases.
  • the invention provides a method of treating pulmonary arterial hypertension comprising treating a subject in need thereof with a therapeutically effective amount of a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the invention provides processes and novel intermediates which are useful for preparing the compounds of Formula I.
  • the present invention comprises compounds of Formula I and pharmaceutically acceptable salts thereof and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amo ⁇ hous forms thereof.
  • the compounds, methods, and formulations comprising Formula I are effective treatments for pulmonary arterial hypertension which encompasses WHO Group I, Group II, Group III, Group IV, and Group V classifications.
  • the instant invention comprises a prodrug compound of Formula I comprising a phenylphosphate group and at least one prostacyclin.
  • the phosphate group of the phenylphosphate is cleaved from the prodrug by a phosphatase in the lung liberating one or more prostacyclins.
  • the compounds of Formula I have the following general features: a. A prostacyclin prodrug represented by
  • the phosphate moiety of the phenylphosphate prodrug of Formula I is efficiently cleaved by a lung phosphatase such as alkaline phosphatase as shown in Scheme A.
  • a lung phosphatase such as alkaline phosphatase as shown in Scheme A.
  • SAl a lung phosphatase
  • SA2 is hydrolyzed either chemically or enzymatically by an esterase to liberate the prostacyclin.
  • the phosphate moiety of the phenylphosphate prodrug of Formula I is efficiently cleaved by a lung phosphatase such as alkaline phosphatase as shown in Scheme B.
  • the resulting intermediate prostacyclin prodrug, SAl in a slower step, is hydrolyzed either chemically or enzymatically by an esterase to liberate the prostacyclin.
  • the prostacyclin prodrug comprising X 2 and/or X 3 may be the same or different from that in X 1 .
  • the compounds of Formula I can release one, two, or three prostacyclins and each of these prostacyclins may be the same or different.
  • each of the prostacyclins comprising X 1 , X 2 or X 3 may be released according to, at least, Scheme A or Scheme B.
  • the prostacyclin comprising X 1 , X", or X may be released in any order or sequence according to, at least, Scheme A or Scheme B.
  • the prostacyclin ester of the prodrug is hydrolyzed chemically or by a lung esterase to give a prostacyclin SC2 and another intermediate phenylphosphate prodrag SCl comprising a prostacyclin as shown in Scheme C.
  • the phosphate group of SCl is cleaved by a lung phosphatase to give a prostacyclin prodrug SC3.
  • the prostacyclin prodrug is then hydrolyzed chemicially or by a lung esterase to give the prostacyclin SC4.
  • X may also comprise a prostacyclin prodrug which may be the same or different prostacyclin comprising X 1 or X 2 . In these embodiments, it is intended that the prostacyclin comprising X 1 , X 2 , and X 3 may be hydrolyzed in any order.
  • the Z and G components comprising the highly polarized linking group represented by primarily determine which of the particular embodiments described in Schemes A-C are operable. The methods of selecting those components are described in the examples herein. Without being bound by theoiy. the combination of the highly polarized linking group and charged phosphate group comprising Formula I produces a highly polarized or charged molecule that interacts with the negative charges on the surface of cell membranes leading to sustained release of prostacyclins.
  • Z is a highly polarized center comprising a nitrogen atom or a sulfur atom that may bear a positive charge.
  • Z is ⁇ (NR l R 2 )A W , N(O)R 1 (N-oxide), S(O) (sulfoxide), S(O) 2 , ⁇ (SR')A H , a heterocyclene comprising ® (NR')A H or ⁇ SA H , or a heteroarylene comprising a NA , wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G ! -0-C(0)-PCY is directly bonded to a
  • Z is ⁇ (NR 1 R 2 JA ⁇ , ⁇ (SR 1 JA ⁇ , a heterocyclene comprising ⁇ (NR ! )A (" > or SA ⁇ , or a heteroarylene comprising a NA ⁇ ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G ' -0-C(O)-PCY is directly bonded to a NR or S of said heterocyclene or a N of said heteroarylene.
  • Z is ⁇ (NR ] R 2 )A (" ⁇ .
  • Z is @ (NR l R 2 )A H and R 1 and R 2 are independently methyl or ethyl.
  • Z is (SR ⁇ A ⁇ .
  • Z is a heterocyclene comprising (NR 1 JA ⁇ wherein the -CH 2 - group of -CH 2 -Z-G'-0-C(O)-PCY is directly bonded to a ⁇ NR 1 .
  • Z is a heterocyclene comprising SA* " * wherein the -CH 2 - group Of -CH 2 - Z-G -0-C(O)-PCY is directly bonded to a S of said heterocyclene.
  • Z is a heteroarylene comprising a NA ⁇ 1 wherein the -CH 2 - group of - CH 2 -Z-G 1 -0-C(O)-PCY is directly bonded to a ® N of said heteroarylene.
  • Z is N(O)R ! (N-oxide).
  • Z is S(O) (sulfoxide).
  • each R 1 and R 2 is, independently, optionally substituted C 1 -C 1O alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - Cio alkynyl, optionally substituted C 3 -C10 carbocyclyl, optionally substituted C 6 -Ci O aryl, or optionally substituted heteroaryl; or R ! and R 2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S, or NR 3 .
  • each R ! is, independently, optionally substituted C 1 -C 1O alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - Cio alkynyl, optionally substituted C 3 -C10 carbocyclyl, optionally substituted C 6 -Ci O aryl, or optionally substituted
  • R 1 and R 2 taken together with the nitrogen to which they are attached form a heterocyclic ring comprising 3-7 carbon atoms wherein one or more carbon atoms of said heterocyclic ring is, optionally, replaced by O, S, or NR 3 .
  • G 1 is independently a bond, optionally substituted C 1 -Ci O alkylene, optionally substituted C 2 -Ci O alkenylene, optionally substituted C 2 -Cio alkynylene, optionally substituted C3 ⁇ Cio carbocyclene, optionally substituted C 6 -C] O arylene, or optionally substituted heteroaryl ene; wherein one or more carbon atoms of said Cj -C 10 alkylene or C 3 -CjO carbocyclene is, optionally, replaced by O, S, NR 3 , -NR 3 C(O)- or -C(O)NR 3 -.
  • G 1 is a bond.
  • G 1 is optionally substituted Cj-Cio alkylene. In another embodiment, G 1 is optionally substituted C 2 -Cs alkylene. In another embodiment, G 1 is optionally substituted C 1 -C 10 alkylene wherein one or more carbon atoms of said C r C ⁇ ) alkylene is replaced by O, S, NR 3 , -NR 3 C(O)- or -C(O)NR 3 -. In another embodiment, G ! is optionally substituted C 2 -C 10 alkenylene. In another embodiment, G is optionally substituted C 2 -Ci 0 alkynylene. In another embodiment, G 1 is optionally substituted C 3 - Cio carbocyclene.
  • G 1 is optionally substituted C J -C JO carbocyclene wherein one or more carbon atoms of said C 3 -Ci O carbocyclene is replaced by O, S, NR 3 , -NR 3 C(O)- or -C(O)NR 3 -.
  • G 1 is optionally substituted C 6 -Ci 0 arylene.
  • G 1 is optionally substituted heteroaryl ene.
  • G 1 is optionally substituted C 2 -C f1 alkylene and Z is (NR 1 R 2 )A (") .
  • G 1 is optionally substituted C- 2 -C 6 alkylene
  • Z is ⁇ (NR 1 R 2 )A (") and each R ! and R 2 is independently methyl or ethyl.
  • each X 2 and X 3 is independently H, F, Cl,
  • Ci-C 3O alkyl optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkyl aryl wherein one to five carbon atoms of said C 1 -C 30 alkyl is optionally replaced by O, S, NR 3 , N(R 3 ) 2 + , or (-OCH 2 CH 2 O-CH- 2 CH 2 O-) n ; and X 1 is -CH 2 -Z-G ⁇ O-C(O)-PCY.
  • X 2 is H, F 5 Cl, Br, optionally substituted Ci-C 30 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Ci-C 30 alkyl is optionally replaced by O, S, NR 3 , N(R 3 J 2 + , or (-OCH 2 CH 2 O-CH- 2CH 2 O-J n ; and each X' and X 3 is independently -CH 2 -Z-G '-0-C(O)-PCY.
  • X 3 is H, F, Cl, Br, optionally substituted Cj-C 3O alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted alkylaryl wherein one to five carbon atoms of said Cj-C 30 alkyl is optionally replaced by O, S, NR 3 , N(R 3 J 2 + , or (- OCH 2 CH 2 O-CH 2 CH 2 O-J n ; and each X ! and X 2 is independently -CH 2 -Z-G '-0-C(O)- PCY.
  • each X 1 , X 2 and X 3 is independently -CH 2 -Z-G '-0-C(OJ-- PCY.
  • X 3 is H and each X 1 and X 2 is independently -CH 2 -Z-G '-0-C(O)-PC Y.
  • X 1 is -CH 2 -Z-G '-0-C(OJ-PCY and PCY is
  • G is O. In another preferred embodiment of this aspect, G 2 is CH 2 . In another preferred embodiment of this aspect, G 5 is a bond. In another preferred embodiment of this aspect, G is -(CH? ⁇ -. In another preferred embodiment of this aspect, G 4 is -CH 2 OCH 2 -. In another preferred embodiment of this aspect, G 4 is -OCH 2 - or -CH 2 O-. In another preferred embodiment of this aspect, X 2 is H. In another preferred embodiment of this aspect, X " is H. In another preferred embodiment of this aspect, each X ⁇ and X J is H, In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A (") . In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A (") . In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A (") . In another preferred embodiment of this aspect, Z is
  • Z is a heterocyclene comprising (NR 1 )A ('] or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G '-0-C(O)-PC Y is directly bonded to a
  • NR 1 of said heterocyclene or a N of said heteroarylene and G 1 is optionally substituted C 1 -C 10 alkylene.
  • X 3 is -CH 2 -Z-G '-0-C(O)-PCY and PCY is
  • G " is O.
  • G 2 is CH 2 .
  • G 5 is a bond.
  • G is -(CH 2 ) ⁇ -
  • G 4 is -CH 2 OCH 2 -.
  • G 4 is -OCH 2 - or -CH 2 O-.
  • X' is
  • X ! is H
  • each X 2 and X s is H.
  • Z is (NR 1 R 2 ) A ('] and G 1 is optionally substituted Ci-C 10 alkylene.
  • G" is O.
  • G 2 is CH 2 .
  • G 5 is a bond.
  • G 4 is -(CEh) 3 -.
  • G 4 is "CH 2 OCH 2 -.
  • G 4 is -OCH 2 - or -CH 2 O-.
  • X ' is H.
  • Z is (NR i R 2 )A (") and G 1 is optionally substituted Ci-Cio alkylene.
  • G is O. In another preferred embodiment of this aspect, G 2 is CH 2 . In another preferred embodiment of this aspect, G 5 is a bond. In another preferred embodiment of this aspect, G 4 is -(CHi) 3 -. In another preferred embodiment of this aspect, G 4 is -CH 2 OCH 2 -. In another preferred embodiment of this aspect, G 4 is -OCH 2 - or -CH 2 O-. In another preferred embodiment of this aspect, X 3 is H. In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A ("> and G 1 is optionally substituted C
  • G" is O.
  • G 2 is CH 2 .
  • G 5 is a bond.
  • G is -(CHi) 3 -.
  • G 4 is -CH 2 OCH 2 -.
  • G 4 is -OCH?- Or-CH 2 O-.
  • Z is
  • NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Cj-Cio alkylene.
  • X " is H. In another embodiment of this aspect, X " is H. In another embodiment of this aspect, each X' and X " is H. In another preferred embodiment of this aspect, Z is (NR 1 R 2 )A ⁇ "> and G 1 is optionally substituted C]-Ci O alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR !
  • X" is H. In another embodiment of this aspect, each X" and X is H. In another preferred embodiment of this aspect, Z is ' (NR R " )A and G 1 is optionally substituted Cj-Cio alkylene. In another preferred embodiment of this aspect, Z is a heterocyclene comprising (NR 1 )A M or a heteroarylene comprising a NA H ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -
  • X ' is H.
  • Z is ® (NR'R 2 )A H and G 1 is optionally substituted Ci-C 10 alkylene.
  • NR of said heterocyclene or a N of said heteroarylene and G is optionally substituted Ci-Cio alkylene.
  • X rl is H.
  • Z is (NR ⁇ R 2 )A (") and G 1 is optionally substituted Cs-Cio alkylene.
  • Z is is a heterocyclene comprising (NR 1 ) ⁇ " - 1 or a heteroarylene comprising a NA ; wherein when Z is said heterocyclene or said heteroarylene the -CH 2 - group of -CH 2 -Z-G l -0-C(O)-PCY is directly bonded to a
  • NR 1 of said heterocyclene or a N of said heteroarylene and G 1 is optionally substituted Q-Cio alkylene.
  • Z is (NR 1 R 2 ) ⁇ and G 1 is optionally substituted Ci-Cjo alkylene.
  • each G 4 is independently optionally substituted C)-Cg alkylene. In another embodiment, each G 4 is independently optionally substituted Ci-Cg alkenylene. In another embodiment, each G 4 is independently optionally substituted C 2 -Cg alkynylene. In another embodiment, each G 4 is independently optionally substituted Cj-Cs alkylene wherein a carbon atom of said optionally substituted Ci-Cg alkylene is, optionally, replaced by O, S, NR " . In a preferred embodiment, each G 4 is independently -(CH 2 )S-. In another preferred embodiment, each G 4 is independently -CH 2 OCH 2 -. In another preferred embodiment, each G 4 is independently -OCH 2 - or -CH 2 O-.
  • each G 5 is independently a bond. In another embodiment each G 5 is independently -CH 2 -.
  • each R 4 is independently
  • each R 5 is independently optionally substituted C)-Cg alkyl. In another preferred embodiment of this aspect, each R 5 is independently optionally substituted C 2 -Cg alkenyl. In another preferred embodiment of this aspect, each R 5 is independently optionally substituted C 2 -Cs alkynyl. In another embodiment, each R 4 is independently optionally substituted C]-Cs alkyl wherein a carbon atom of said optionally substituted Ci-Cg alky] is, optionally, replaced by O, S, NR 3 . In another preferred embodiment of this aspect, each R 5 is independently - (CHo) 4 CHa. In another preferred embodiment of this aspect, each R ⁇ is independently
  • each R 4 is independently OH .
  • each R 5 is independently optionally substituted Ci-Cs alkyl.
  • each R 5 is independently optionally substituted C 2 -Cs alkenyl.
  • each R is independently optionally substituted C?-Cs alkynyl.
  • each R 4 is independently optionally substituted C 1 -C 8 alkyl wherein a carbon atom of said optionally substituted Ci-Cg alkyl is, optionally, replaced by O, S, NR .
  • each R is independently - (CHb) 4 CH 3 .
  • each R 5 is independently
  • each PCY is independently
  • each R is independently selected from
  • each R is
  • each R is
  • each R is
  • each PCY is independently
  • each R is independently selected from
  • each R is
  • each R is OH . In another embodiment of this aspect, each R is
  • each PCY is independently
  • each R 4 is independently selected from
  • each R 4 is
  • each R is . In another embodiment of this aspect, each R is A
  • each PCY is independently .
  • each R is independently selected
  • each R is
  • each R is
  • each PCY is independently .
  • each R 4 is independently selected from
  • each R is
  • each R is
  • each PCY is independently
  • each R is independently selected
  • each R is
  • each R is
  • each R 4 is
  • L is O. In another embodiment, L is -
  • Formula I is a compound or pharmaceutically acceptable salt thereof selected from
  • the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, suitable for treating PAH.
  • Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation.
  • the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 ⁇ m.
  • MMAD mass median aerodynamic diameter
  • the compound of Formula 1 is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).
  • Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate or equivalent nebulizers.
  • a jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets.
  • a vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.
  • compositions of the invention described above provide the drug formulated in a solution permitting delivery of a therapeutically efficient amount of the drug by nebulization provided that the aerosol generated by the nebulization meets criteria required for efficient delivery. Therefore, the nebulizer which aerosolizes the formulation of a compound of Formula I becomes an important feature of the invention.
  • the formulations which can be efficiently nebulized must contain small amounts of the compounds of Formula I which are delivered in small volumes and conform to certain ranges of pH and osmolality.
  • the compound of Formula I is preferably dissolved in a minimal volume of about 0.5 to about 7 niL of an aqueous solvent having a pH between about 4.5 and about 7.5 and comprising chloride, bromine or iodine ions.
  • the formulation has a shelf-life between about one and about two years.
  • the aqueous formulation of a compound of Formula I is prepared just prior to administration to assure the stability of the compound of and to assure a commercially acceptable shelf life of the drag.
  • the fo ⁇ nulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 ⁇ m and about 5 ⁇ m using a nebulizer able to aerosolize the formulation of the compound of Formula I into particles of the required MMAD.
  • a nebulizer able to aerosolize the formulation of the compound of Formula I into particles of the required MMAD.
  • the majority of aerosolized particles should not have a MMAD greater than about 5 ⁇ m. If an aerosol contains a large number of particles with a MMAD larger than 5 ⁇ m, the particles are deposited in the upper airways decreasing the amount of drug delivered to the optimal site of action in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 ⁇ m , then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
  • the solution or diluent used for preparation of the aerosol formulation of a compound of Formula I has a pH range from about 4.5 to about 7.5, more preferably between about 5.5 and about 7.0.
  • the pH of the formulation is an important feature for aerosolized delivery of the compounds of Formula I.
  • the aerosol is either acidic or basic, it can cause bronchospam and cough. Any aerosol with a pH of less than 4.5 typically induces bronchospasm. Aerosols with a pH between 4.5 and 5.5 will cause bronchospasm occasionally. Any aerosol having pH greater than 7.5 is to be avoided as the body tissues are unable to buffer alkaline aerosols.
  • Aerosols with controlled pH below 4.5 and over 7.5 result in lung initiation accompanied by severe bronchospam cough and inflammatory reactions.
  • aqueous formulations outside this pH range may contribute to more rapid degradation of the compounds of Formula I by increasing the cleavage of the esters, carbonate, and solvolytically labile groups in the compounds. Consequently, in a preferred embodiment, the aerosol formulation of a compound of Formula I is adjusted to a pH between about 4.5 and about 7.5 with a more preferred pH range from about 5.5 to about 7.0.
  • a particularly preferred pH range is about 5.5 to about 6.5.
  • Formula 1 may require adjustment of the osmolality of the aerosol formulation to emulate the physiological conditions found in the healthy lungs.
  • Bronchospasm or cough reflexes may not be totally repressed at the osmolality of the diluent for aerosolization, however, they can be sufficiently controlled and/or suppressed when the osmolality of the diluent is in a certain range.
  • the given osmolality controls bronchospasm and the chloride concentration, as a permeant anion, controls cough.
  • formulations for nebulization of compounds of Formula I will have an osmolality between about 50 and about 1200 m ⁇ sm/kg.
  • chloride ion or another anion may need to be added for successful and efficacious delivery of aerosolized compounds of Formula 1 but the amount may be lower than amounts provided and typically used for aerosols of other compounds.
  • the chloride anion can be substituted with bromine or iodine anions, since both are permeant anions.
  • bicarbonate may be wholly or partially substituted for chloride ion.
  • the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the compound of Formula 1 to the lung sufficient to promote pulmonary vasodilation and treat PAH.
  • the amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula I.
  • a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of Formula 1 into the airways.
  • at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof is delivered as a dry inhalable powder.
  • the compounds of the invention are administered endobronchially as a dry powder formulation to efficaciously deliver fine particles of compound into the endobronchial space using dry powder or inetered dose inhalers.
  • the compound of Formula I is processed into particles with, predominantly, MMAD between about 1 ⁇ m and about 5 ⁇ m by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 ⁇ m and about 5 ⁇ m are well know in the art.
  • excipients are added to the compound of Formula I before processing into particles of the required sizes.
  • excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.
  • Particle size determinations are made using devices well known in the art.
  • a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.
  • a compound of Formula I is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices.
  • dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; US5,522,385; US4,6 ⁇ 8,218; US4,667,668; US4, 805,81 1 and US5, 388.572.
  • dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; US5,522,385; US4,6 ⁇ 8,218; US4,667,668; US4, 805,81 1 and US5, 388.572.
  • One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber.
  • the second design is a factory-metered device in which each individual dose has been manufactured in a separate container. Both systems depend on the formulation of the drug into small particles of MMAD from 1 ⁇ m and about 5 ⁇ m, and often involve co-formulation with larger excipient particles such as, but not limited to, lactose.
  • Drag powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity.
  • Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of 1 ⁇ m to about 5 ⁇ tm.
  • a compound of Formula I is delivered as a dry powder using a metered dose inhaler.
  • metered dose inhalers and devices include those disclosed in US5,261 ,538; US5,544,647; US5,622,163; US4,955,371 ; US3,565,070; US3,36130 ⁇ and US6, 116,234.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 ⁇ m.
  • the compounds of Formula I are useful for treating pulmonary arterial hypertension.
  • the amount of active ingredient that may be combined with the excipients to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, is dosed in a therapeutically effective amount ranging from about 10 to about 5000 ⁇ g.
  • the dose will be determined by the host treated and the severity of the disease as determined by those physicians skilled in the art.
  • the drug will be administered four, three, two, or most preferably once a day.
  • a combination of an aerosol formulation of a compound of Formula I and a device significantly enhances the efficiency and speed of drug administration.
  • the average time for administration of other aerosolized drugs is 15-20 minutes per dose.
  • the time required for this treatment represents a significant burden to the patient and contributes to reduced compliance with the recommended dosage regimen.
  • the aerosolizable formulation of a compound of Formula I is delivered by a device capable of delivering a therapeutically effective dose in less than 15 minutes, more preferably in less than 10 minutes, and most preferably in less than 5 minutes,
  • a compound of the invention or “a compound of Formula I” means a compound of Formula 1 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.
  • Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • an alkyl group can have 1 to 30 carbon atoms (i.e, Cj-C 3O alkyl), 1 to 10 carbon atoms (i.e., Ci-C 10 alkyl), or 1 to 6 carbon atoms (i.e., Ci-C 6 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 J 2 ), 1 -butyl (n-Bu, n-butyl.
  • alkenyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 2 O alkenyl), 2 to 12 carbon atoms (i.e.. C 2 -C] 2 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • Alkynyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 2 O alkynyl), 2 to 12 carbon atoms (i.e., C 2 -C] 2 alkyne,), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl).
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1 -ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyI (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1 ,3-propyl (-CH 2 CH 2 CH 2 -). 1 ,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkenyl ene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkenyl ene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • uArylalkyI refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical that is optionally substituted.
  • Typical arylalkyl groups include, but are not limited to, benzyl. 2 -phenyl ethan-1-yl, naphthylmethyl, 2-naphthylethan-l -yl, naphthobenzyl, 2-naphthophenyIethan-l -yl and the like.
  • the arylalkyl group can comprise 7 to 26 carbon atoms, e.g., the alkyl moiety is 1 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp 2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • the arylalkenyl group can comprise 8 to 26 carbon atoms, e.g., the alkenyl moiety is 2 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • “Arylalkynyl” refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 8 to 26 carbon atoms, e.g., the alkynyl moiety is 2 to 12 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • substituted in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc.
  • substituted alkyl means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH 3 , etc.), an amine (e.g., -NHCH 3 , -N(CHs) 2 , etc.), or a thioalkyl group (e.g., -SCH 3 ).
  • the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -O-CH 3 , etc.), an alkyl amine (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.), or a thioalkyl ether (e.g.,-CH 2 -S-CH 3 ).
  • an alkyl ether e.g., -CH 2 CH 2 -O-CH 3 , etc.
  • an alkyl amine e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.
  • a thioalkyl ether e.g.,-CH 2 -S-CH 3
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH 2 CH 2 -OH), an aminoalkyl group
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a Cj-C f , heteroalkyl group means a heteroalkyl group having 1 to 5 carbon atoms.
  • Heterocyde or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern
  • heterocycle includes a "carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
  • heterocycle or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings).
  • Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups,
  • a non-limiting example of a carbonyl substituted heterocyclyl is:
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrol yl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indole ⁇ yl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl.
  • pyrrolidinyl 2-pyrrolidonyl
  • pyrrolinyl tetrahydro furanyl
  • tetrahydroquinolinyl tetrahydroisoquinolinyl
  • decahydroquinolinyl octahydroisoquinolinyl
  • azocinyl triazinyl, 6H-L2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl
  • pyranyl isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H ⁇
  • carbon bonded heterocyclics are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetraliydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5 -pyridazinyl, 6-pyridazinyl, 2 -pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, ⁇ -pyrimidinyl, 2 -pyrazinyl, 3 -pyrazinyl, 5-pyrazinyl, 6- pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2 -imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1 -aziridyl, 1 ⁇ azetedy], 1 -pyrrol yl, 1-imidazolyl, 1-pyrazolyl, and l-piperidinyl.
  • Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CHb-, 2-(heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry.
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolyl methyl, oxazolylmethyl, thiadiazolylm ethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylniethyl, pyridinylm ethyl, pyridizylm ethyl, pyrimidylmethyl, pyrazinylm ethyl, etc.
  • heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolyl methyl, oxazolylmethyl, thiadiazolylm ethyl, etc.
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp" carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - alkenyl ene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 6 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • Heterocyclyl alkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp J carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - alkynylene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkynyl group comprises 6 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • suitable heteroaryl rings include all of those listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • Carbocycle or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), paitially unsaturated ⁇ e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings.
  • Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, 1- cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohcxyl, 1-cyclohcx-l -cnyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl.
  • Non-limiting examples of bicyclo carbocycles includes naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, and indanyl.
  • Carbocyclene refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic radical as described for "carbocycle” having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent carbocycle.
  • Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene-
  • Heteroarylalkyl refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • Non-limiting examples of heteroarylalkyl include -CH 2 -pyridinyl, -CEb-pyrrolyl, -CHi-oxazolyl, -CH 2 -indolyl, -Ctb-isoindolyl, -C Hi-purinyl, -CH ⁇ -furanyl, -CH ⁇ -thienyl, -CH 2 -benzofuranyl, -CHb-benzothiophenyl, -CH 2 -carbazolyl, -CH 2 -imidazolyl, -CHi-thiazolyl, -Ctk-isoxazolyl, -CH 2 -pyrazolyl, -CH 2 -isot hiazolyl, -CH?-quinolyl,
  • Linker or "link” means a chemical moiety comprising a covalent bond or a chain of atoms. Unless otherwise specified, the carbon atoms of this invention are intended to have a valence of four. In some chemical structure representations where carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substitutents needed to provide a valence of four should be assumed to be hydrogen. For example, 0H has the same meaning as
  • any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na + , Li + , K + ' Ca + ⁇ and Mg + ⁇ ), ammonium and NR 9 4 + (wherein R 9 is Ci-C 4 alkyl).
  • Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene-l ,5-disulfonic acid, polygal
  • Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NR 4 + (wherein R 10 is independently selected from H or a Ci-C 4 alkyl group).
  • Certain embodiments of Formula I comprise positively charged quaternary N and ternary S atoms which will have a negative counter ion A (" ⁇ . It is intended that the negative counter ions A ⁇ will be pharmaceutically acceptable.
  • Non-limiting examples of pharmaceutically acceptable negative counter ions comprise the anions of organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, naphthalene- 1,5-disulfonic acid, polygalacturonic acid, malonic acid, sulf
  • salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mii ⁇ or images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • a compound of Formula 1 and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures.
  • the crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conform ers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conform ers of the same molecule (conformational pseudopolymorphism).
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula 1 and their pharmaceutically acceptable salts.
  • a compound of Formula I and its pharmaceutically acceptable salts may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents, may be used to create the amorphous forms of the instant invention.
  • the instant invention comprises all amorphous forms of the compounds of Formula I and their pharmaceutically acceptable salts.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • terapéuticaally effective amount is the amount of compound of Formula I present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by inhalation.
  • the precise amount will depend upon numerous factors, for example the particular compound of Formula I, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.
  • variable PCY comprises a prostacyclin or carbaprostacyclin or a derivative thereof. Any reference to the term “prostacyclin” herein, is intended to encompass the terms prostacyclin, carbaprostacyclin, or a derivative of either.
  • normal saline means water solution containing 0.9% (w/v) NaCl.
  • diluted saline means normal saline containing 0,9% (w/v) NaCl diluted into its lesser strength.
  • quarter normal saline or "14 NS” means normal saline diluted to its quarter strength containing 0.225% (w/v) NaCI.
  • MMAD mass medium aerodynamic diameter.
  • predominantly means including at least 70% but preferably 90% of particle sizes between 1 ⁇ m and 5 ⁇ m.
  • mutant prodrug refers to a bipartite or tripartite prodrug in which specific bond(s) of the compound are broken or cleaved by the action of an enzyme or by biological process thereby producing or releasing a drug and the carrier which is a synergistic drug of the drug to which it is linked.
  • the present invention also relates to the processes for preparing the compounds of the invention and to the synthetic intermediates useful in such processes, as described in detail below.
  • 1,2,2,6,6-Pentamethylpiperidine (23 ⁇ L, 126 ⁇ mol) and methanesulfonyl chloride (5.5 ⁇ L, 69 ⁇ mol) were added to a stirring solution of compound represented in Exampie 5 (20 mg, 63 ⁇ mol) in CH 2 Cl 2 (0.6 mL) at 0 0 C.
  • the reaction mixture was stirred for 2 h at 22 0 C then quenched with 10 % (w/v) citric acid (2 mL) and the aqueous was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with satd. NaHCO 3 (3 mL), brine (3 mL), dried over Na?S ⁇ 4 , and concentrated.
  • the title compound is synthesized using terf-butyldimethylsilyl chloride (3 equiv.) and imidazole (4 equiv) to a solution of iloprost in dichlorm ethane.
  • the title compound is synthesized using /erf-butyldimethylsilyl chloride (3 equiv.) and imidazole (4 equiv) to a solution of treprostinil in dichlormethane.
  • Blood samples (approximately 2 mL, or as much as possible) were collected from 6 animals per time point via cardiac puncture (following euthanasia via CO 2 inhalation) into tubes containing K2EDTA. All blood samples were placed on wet ice (or an ice block) following collection. The samples were centrifuged and the plasma was separated and stored frozen at approximately -7O 0 C until analysis. Immediately following blood collection, the lungs from each animal were removed, blotted dry, weighed, and homogenized with 5 mL of 20 mM aqueous sodium EDTA solution on ice. The homogenate was stored at approximately -7O 0 C until analysis. Intratracheal Dosing Procedure
  • the animals were anesthetized with isofhirane vapors utilizing a precision vaporizer (3-5%, 5 to 10 minutes).
  • the rat was suspended by the upper incisors on an incline rack in a supine position. And the rat's tongue was gently retracted to the side to allow access to the back of the throat, which was illuminated with an appropriate lighting device.
  • a Penn CenturyTM Microsprayer ® (Model IA-I B), was attached to a glass tuberculin syringe, was visually inserted into the trachea. Placement in the airway was confirmed by "pulling/pushing" the barrel of the glass syringe.
  • a vacuum or resistance of the barrel indicated that the cannula was in the esophagus. If this occured, the Microsprayer was removed and the procedure reinitiated. No resistance of the barrel assured placement in the airway, and the glass syringe was removed.
  • a luer-lock tip syringe (containing the appropriate volume of test article and approximately 0.1 niL of air) was attached to the Microsprayer, with the air in the syringe displaced above the test article, allowing for full delivery of the test article.
  • the test article was delivered into the airways by pushing the plunger of the syringe on inhalation.
  • the rat remained suspended on the incline rack for an additional 10 to 20 seconds to allow further distribution of the test article into the lungs.
  • Example 9 was administered to rats by the intratracheal route (0.5 mg/kg) and was efficiently cleaved to Example 2 in vivo.
  • lung concentrations of tetrahydro PG12 produced from the prodrug were much higher for 4 hours in the lung with a Cmax of 8 micrograms/g whereas the lung concentration of tetrahydro PGI2 given directly was rapidly cleared ( ⁇ 300 ng/g).

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Abstract

La présente invention concerne des promédicaments phénylphosphonates comprenant une ou plusieurs prostacyclines destinés au traitement de l'hypertension artérielle pulmonaire. L'invention concerne également des formulations inhalables des promédicaments pour une administration par production d'aérosols ou de poudre sèche. Les composés et les formulations sont utiles pour produire une vasodilatation pulmonaire et pour traiter l'hypertension artérielle pulmonaire.
PCT/US2009/046764 2008-06-10 2009-06-09 Promédicaments inhalés à base de carbaprostacyclines et de prostacyclines destinés au traitement de l'hypertension artérielle pulmonaire Ceased WO2009152160A1 (fr)

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WO2017205392A1 (fr) 2016-05-24 2017-11-30 Amgen Inc. Composés de carfilzomib pégylés
WO2018058124A1 (fr) * 2016-09-26 2018-03-29 United Therapeutics Corporation Promédicaments de tréprostinil
WO2019099715A1 (fr) 2017-11-16 2019-05-23 Amgen Inc. Compositions stables de composés carfilzomib pégylés
US10343979B2 (en) 2014-11-18 2019-07-09 Insmed Incorporated Methods of manufacturing treprostinil and treprostinil derivative prodrugs
JP2019519489A (ja) * 2016-05-05 2019-07-11 リクイディア・テクノロジーズ・インコーポレーテッド 肺高血圧症を治療するための乾燥粉末トレプロスチニル
US20190321290A1 (en) * 2016-01-29 2019-10-24 Mannkind Corporation Composition and method for inhalation
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US11458098B2 (en) 2019-04-29 2022-10-04 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof

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